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Global Translational Medicine Anti-inflammatory therapy in CVD

program includes pivotal trials, such as the BROADWAY diabetes. Despite its established role in autoimmune
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trial, which showed a 33% reduction in LDL levels and a disease, methotrexate failed to reduce IL-1β, IL-6, or CRP
21% reduction in major adverse cardiovascular events levels and had no significant impact on cardiovascular
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(MACE) after 1 year. The BROOKLYN trial demonstrated outcomes. The primary endpoint occurred in an incidence
a 41.5% reduction in LDL levels in heterozygous familial rate of 4.13 versus 4.31/100 person-years in the methotrexate
hypercholesterolemia patients at 1 year. 20 and placebo groups, respectively (hazard ratio [HR]: 0.96;
95% confidence interval [CI]: 0.79 – 1.16). These findings
6. Eicosapentaenoic acid (EPA) and its anti- suggest that non-specific immunosuppression may not be
inflammatory benefits effective in atherosclerosis.

EPA is crucial to cardiovascular health due to its anti- In contrast, in post-myocardial infarction patients,
inflammatory and cardioprotective properties. It the LODOCO trial demonstrated a 24% reduction in
integrates into cell membranes, replacing arachidonic MACE with colchicine 0.5 mg daily treatment (HR: 0.76;
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acid, a precursor to pro-inflammatory eicosanoids, such 95% CI: 0.61 – 0.95). Building on this, the COLCOT
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as prostaglandins and leukotrienes. This shift reduces the assessed colchicine’s efficacy when initiated within 30-day
production of inflammatory molecules and promotes the post-myocardial infarction, showing a 23% reduction
synthesis of anti-inflammatory mediators, such as resolvins, in cardiovascular events (HR: 0.77; 95% CI: 0.61 – 0.96),
which are essential for resolving chronic inflammation. In particularly in stroke and urgent revascularization,
addition, EPA downregulates key inflammatory cytokines, reinforcing its role in post-myocardial infarction
including TNF-α, IL-1, and IL-6, by inhibiting the nuclear management. 23
factor kappa B (NF-κB) pathway, a major regulator of The CANTOS trial explored anti-inflammatory therapy
inflammation. using canakinumab, a monoclonal antibody against

The Reduction of Cardiovascular Events with Icosapent IL-1β. In patients with elevated hs-CRP levels following
Ethyl-Intervention Trial showed that high-dose icosapent myocardial infarction, treatment with canakinumab at
ethyl led to a 25% reduction in MACE, including a 20% 150 mg every 3 months reduced cardiovascular events
decrease in cardiovascular mortality and a 31% reduction by 15% (HR: 0.85; 95% CI: 0.74 – 0.98; p=0.021) and
in myocardial infarction incidence. The trial also showed cardiovascular mortality by 21% (HR: 0.79; 95% CI:
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a significant reduction in inflammatory marker levels, with 0.67 – 0.93; p=0.005). However, it did not reduce all-
hs-CRP levels decreasing by 19% and IL-6 levels by 10%. cause mortality (HR: 0.94; 95% CI: 0.83 – 1.06) and was
associated with an increased risk of fatal infections, raising
7. Clinical trials using anti-inflammatory concerns about the safety of broad immune suppression.
agents in CVD prevention (CURT > low- The ZEUS trial is a randomized, double-blind
dose colchicine [LODOCO], colchicine cardiovascular outcomes study evaluating ziltivekimab,
cardiovascular outcomes trial [COLCOT], a monoclonal antibody that selectively inhibits IL-6,
canakinumab anti-inflammatory in patients with chronic kidney disease and ASCVD
with elevated hsCRP levels ≥2 mg/L. Given the high
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thrombosis outcomes study [CANTOS], cardiovascular risk in this population, particularly for
stabilization of plaques using darapladib- those who cannot tolerate colchicine, the trial aims to
thrombolysis in myocardial infarction determine whether monthly subcutaneous ziltivekimab
[SOLID TIMI], and losmapimod in 15 mg treatment can reduce MACE. Secondary endpoints
myocardial infarction 60 [LATITUDE TIMI]) assess kidney function decline, dialysis initiation, and
mortality related to cardiovascular or renal causes. With
Key clinical trials, including the Cardiovascular more than 6,200 participants and a target of 1,044 primary
Inflammation Reduction Trial (CIRT), the LODOCO, outcomes, the ZEUS trial is powered to detect a 20%
the COLCOT, the CANTOS, the SOLID-TIMI 52, and relative risk reduction in MACE. This study builds on prior
the LATITUDE-TIMI 60 trials, have explored various evidence linking IL-6 to atherogenesis and inflammation,
inflammatory pathways in atherosclerosis and their impact potentially establishing ziltivekimab as a novel anti-
on cardiovascular outcomes (Table 1). inflammatory strategy for high-risk patients.
The CIRT, a randomized placebo-controlled trial, The SOLID-TIMI 52 trial evaluated darapladib, a
examined low-dose methotrexate (15 – 20 mg weekly) in selective inhibitor of lipoprotein-associated phospholipase
patients with prior myocardial infarction or multivessel A2, hypothesizing that reducing plaque necrosis would
coronary artery disease with metabolic syndrome or lower cardiovascular risk. Despite its mechanistic rationale,

Volume 4 Issue 3 (2025) 16 doi: 10.36922/GTM025100024